UA81948C2 - Transdermal device for treating urine incontinence containing fezoterodin in polymeric matrix - Google Patents

Abstract

The invention relates to a device for transdermally administering a compound of formula (1), wherein A represents hydrogen or deuterium, R represents a group selected among C-Calkyl, С-Сcycloalkyl, or phenyl, each of which can be substituted by C-Calkoxy, fluoride, chlorine, bromine, iodine, nitro, amino, hydroxy, oxo, mercapto, or deuterium, the С atom marked by і * (asterisk) being provided in the R configuration. The invention is characterized in that the compound of general formula (I) is provided in a polymer matrix and is released at a dose of 0.5 to 20 mg per day through human skin. The invention further relates to the use of said compounds of formula (I) for producing transdermal medicaments.

Description

Description of the invention

The present invention relates to a medicinal product for transdermal administration of complex 2(k)-3,3-diphenylpropylaminomonoesters, as well as their use for the preparation of a medicinal product intended for transdermal administration.

Over the past 50 years, the share of elderly people in the total population has increased significantly. The most common diseases of people of this group, associated with age-related changes in the body, include disorders of the urinary bladder. That is why the development of the most effective and gentle therapy for bladder diseases is becoming more and more important.

In case of urge incontinence, the disorder of the bladder function is caused by a violation of the function of its muscles.

The cause of this disorder in many cases is stimulation, or hyperactivity of muscarinic receptors. Therefore, for the therapy of overactive bladder and related symptoms, such as increased urge to urinate, incontinence, pollakisuria or nocturia, it is desirable to use 12 antimuscarinic active substances tolterodine and oxybutynin.

Oxybutynin is an effective antimuscarinic active substance, the use of which, however, is accompanied by significant side effects. At the same time, we are primarily talking about severe dryness in the mouth, which causes extremely unpleasant sensations in many patients.

The advantage of tolterodine is that, unlike oxybutynin, it has a lower incidence of muscarinic side effects. In the body, tolterodine is dealkylated mainly under the action of isoenzyme 206 of cytochrome P-450, turning into the main active metabolite 2-I3-(1,1-diisopropylamino)-1-phenylpropyl|-4-(hydroxymethyl)phenol, and under the action of isoenzyme ZA4 of cytochrome P -450 is slowly dealkylated, turning into an inactive metabolite.

Since tolterodine is metabolized exclusively under the action of cytochrome P-450 isoenzymes, there is a potential danger of interaction of tolterodine with other active substances, which is accompanied by their decomposition, for example, with warfarin (Soiissi, Appaiz oi Rpagtasoipegaru 33, 1999, p. 1173), with antifungal agents, such as ketoconazole |Vguppe, Vg. ). Siip. Rpaptosai 48, 1999, p. 564), with macrolide antibiotics or with protease inhibitors. A similar danger exists primarily in the so-called "slow metabolizers" (people with reduced activity of the cytochrome P450 system) with a deficiency of isoenzyme 206, in whose body tolterodine is metabolized exclusively under the action of the ZAA4 isoenzyme and in whose plasma tolterodine is present, respectively, in a much higher concentration.

In Izayavka MUO 99/58478| described new derivatives of 3,3-diphenylpropylamine as muscarinic active substances. Me,

The 3,3-diphenylpropylamine derivatives offered in this publication are prodrugs of 2-3-(1,1-isopropylamino)-1-phenylpropyl|-4-(hydroxymethyl)phenol, which are hydrolyzed when passing through biological membranes and in plasma esterases Thus, it is possible to avoid the decomposition mechanism dependent on the 206 so isozyme.

Therefore, such 3,3-diphenylpropylamine derivatives, for example, 2-I3-(1,1-isopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenylisobutyrate (INN: fesoterodine), unlike tolterodine, are not prone to accumulation in in the body, including in the body of "slow 50 metabolizers", do not interact with inducers, respectively inhibitors of cytochrome P-450 and have a better set of properties that determine the safety of their use from the point of view of their potential interaction with other active substances and their accumulation in the body.

Taking into account the above, the advantages of the 3,3-diphenylpropylamine derivatives described in (MUO 99/58478), primarily the advantages of fesoterodine, and the need for their development was determined. It is the peculiarities of the metabolic pathway of tolterodine and the disadvantages of oxybutynin (dry mouth) that explain the need of medicine for a co-medicinal agent that does not have the disadvantages of both of the above-mentioned substances. - Complex 3,3-diphenylpropylaminomonoesters can be presented in the form of their stable crystalline salts. Fesoterodine hydrofumarate is their best example. Similar salts described in (MO 01/35957| and re) are suitable primarily for oral and parenteral therapy of overactive bladder. 20 Despite the fact that oral administration of these compounds is optimal for most patients, it is often necessary to introduce them into the body by another route. This need is not least due to elderly patients suffering from motility disorders of the bladder and oral administration of which medicines may be impossible or unacceptable for a number of reasons.

So, in particular, patients of the specified age group often suffer from many diseases and therefore 29 take several different medicines at the same time. In order to avoid interactions with other drugs during their resorption and/or excessive load on the gastrointestinal tract and liver caused by taking additional drugs, it is often necessary to introduce them into the body, bypassing the gastrointestinal tract and the liver, in which primary metabolism occurs (the so-called effect of primary passage through the liver), and thus in the use of a non-oral dosage form. 60 In addition, many elderly patients may have difficulty swallowing solid dosage forms, while other elderly patients may have impaired gastrointestinal absorption, for example, due to acute or chronic gastrointestinal diseases or taking antibacterial agents.

In addition, the use of a dosage form that avoids primary metabolism in the liver, according to the effect of primary passage through the liver and which, in addition, has the effect of slow release of the active substance from it, allows you to maintain the concentration of the active substance in the plasma at a constant level, which in general helps reduce the risk of unwanted side effects, primarily dry mouth, while maintaining or even increasing clinical effectiveness.

Transdermal administration of a complex 3,3-diphenylpropylaminomonoester, primarily fesoterodine, is advisable because it avoids, for example, an increase in plasma concentration to peak values inherent in oral administration of active substances and the associated danger of muscarinic side effects, primarily dry mouth .

The possibility of delivering the active substance into the circulatory system over a longer period of time in the most uniform amount would allow to increase the total daily dose of the active substance and its effectiveness and at the same time reduce the likelihood of unwanted side effects.

The basis of this invention was the task of offering a device, respectively a drug for transdermal introduction into the body of compounds of the general formula I, which satisfy the following requirements: 1. the device should provide the possibility of transdermal introduction into the body of complex 3,3-diphenylpropylaminomonoester in a therapeutically effective daily dose; 2. after the initial application of the medicinal product to the skin, the active substance must be transported through it in a therapeutically effective amount for a longer period of time, that is, for at least 24 hours, preferably for 48 or 72 hours;

C. the active substance should enter the body, penetrating through the skin, if possible at a constant rate in order to maintain its concentration in the plasma at an approximately constant level during only 2 hours of the intended use of the medicinal product; 4. the maximum area of the skin surface in contact with the device (for example, patch) should preferably be 5Osm?; 5. if possible, the use of percutaneous absorption activators should be avoided; 6. the device should be as simple as possible and should be economical to manufacture. with

The suitability of such a transdermal medicinal product for controlled, preferably multi-day, introduction of the active substance into the body is determined, however, by a large number of different parameters and requirements and, and) in particular, - the type of transdermal dosage form (ointment, gel, patch, aerosol), - release control of the active substance (passive diffusion, iontophoresis, ultrasound, electroporation), with - the concentration of the active substance in the dosage form, its capacity for the active substance and the degree of its saturation with the active substance, - - the ability of the active substance to penetrate the skin in conditions of occlusion, for example, after application patch on the skin, - the principle of retardation (slowing down the release of the active substance), which is used to "-- ensure the continuous penetration of the active substance through the skin in a stable mode for one day or several days, - the features of the technology of manufacturing the dosage form, - the required daily dose of the active substance, - using the active substance in o physical form (base, salt, aggregate state, optical configuration). According to this, a drug for controlled transdermal introduction of an active substance into the body is an extremely complex system in which the properties of the active substance and its penetration through the skin are often unpredictably influenced by a large number of various factors.

Therefore, despite all the many years of attempts made in the pharmaceutical industry, not a single dosage form for transdermal introduction of muscarinic into the body has been released to the market until now.

Go! active substance, for example, oxybutynin or tolterodine.

Transdermal administration of 2-I3-(1,1-diisopropylamino)-1-phenylpropyl|-4-(hydroxymethyl)phenol, which is the main metabolite of tolterodine, due to its extremely low rate of penetration through human skin is also a problem , which is not so easily resolved clinically (see Table 1).

In Izayavka MUO 99/58478| the basic ability of complex 3,3-diphenylpropylaminomonoethers to penetrate through the skin is indicated, if a solution of this substance is tested by the Tpietezzep |Asia Rpat method. Thespians 34, "about 1999, p.991. However, in (MO 99/58478)| there is no information about what performance a device for transdermal introduction of complex 3,3-diphenylpropylaminomonoesters into the body should have, in order to ensure the long-term percutaneous entry of these active substances into the body of patients, if possible with a constant speed.

In addition, according to the results of a series of time-consuming measurements, transdermal dosage forms made with (F) using the highly pure salts of complex 3,3-diphenylpropylaminomonoesters known from (МО 99/58478) were found to be unsuitable for therapeutic use due to the too low rate of penetration of these active substances skin (table 1). In accordance with the invention, it was unexpectedly established that the compound of the general formula b5 and iii and x

ХХ " 5 M in which A is hydrogen or deuterium, and K is a group selected from C-alkyl, C3-isodichloroalkyl, and phenyl, each of which may be substituted with fluorine, chlorine, bromine, iodine, hydroxy, oxo, or deuterium , and in which the C-atom marked with the symbol "" (asterisk) is in the (K)-configuration, can be transported through the human skin with a constant rate of penetration through it in an amount sufficient for the therapeutic treatment of overactive bladder, which is from 0.5 to 20 mg, over a period of at least 24 hours, if the compound of the general formula I! in the form of a free base is introduced in a sufficient amount into the polymer layer, preferably into the polymer layer, which is capable of self-adhesive, (adhesive matrix), Ge) of the transdermal device.

With the help of something like this, which has a simple design of a flat-shaped device with a maximum surface area of about 50 cm? unexpectedly, it turned out to be possible to transdermally introduce compounds of the general formula I into the body in the clinically necessary dosage range.

Accordingly, the object of the invention is a device for transdermal administration of compounds of the formula (22) into the body

From co

F -

She, . "" Kh

M so - so in which A is hydrogen or deuterium, and K is a group selected from C--Salkyl, C3-Siodichloroalkyl, and n»20 phenyl, each of which can be substituted by a C-Salkoxy group, fluorine, chlorine, bromine, iodine, nitro group, amino group, hydroxy group, oxo group, mercapto group or deuterium, and in which the C atom indicated by the symbol "" with (asterisk) is in the (K)-configuration, which differs in that the compound of the general formula is in dissolved or in a dispersed form in a polymer layer, which is preferably capable of self-adhesive, a polymer layer (adhesive matrix), and is released from it with a rate of penetration through human skin from 29 0.5 to 20 mg per day.

GF! In the best version, the active substance is introduced into the polymer layer, for example, the adhesive matrix, in the form of a free base. ko The term "free base" according to the invention means that the compound of the general formula | presented in the form of a salt of less than 20 wt.95, better less than 10, 5 or Zwt.95, especially better less than Imas.9o. because the Introduction of the known from MUO 01/35957| high-purity salts of 3,3-diphenylpropylamine derivatives, for example, fesoterodine fumarate, in the polymer layer does not allow to achieve a therapeutically satisfactory rate of their entry into the body when transdermally administered. Mixing charged molecules such as silicates or chitosan into the matrix containing the active substance, as well as agents that intensify the penetration of the active substance through the skin, called percutaneous absorption activators, such as oleic acid or propylene glycol monolaurate (PGML ), also does not allow to achieve a satisfactory rate of penetration of the active substance through the skin (table 1).

The release of the base from the appropriate salt by adding calcium silicate during the preparation of the adhesive matrix, as described in (MO 94/07486), usually also does not provide the necessary rate of penetration of the active substance through the human skin (table 1). This is due to the fact that such a transformation of the salt into the free base of the drug, as a rule, is not completed completely, as a result of which too much of the active substance is present in the matrix in a protonated form.

Therefore, in the manufacture of the devices proposed in the invention, a compound of the general formula | mass should be added to the forming polymer matrix already in the form of a free base. In compliance with this condition, all tested /o matrices provided the therapeutically necessary rate of penetration of the active substance through the skin (table 1).

Batch Mo Contact Method Content of the active substance (wt.95 | Specific mass of processing glue / fesoterodin) of the matrix (g/m?) | constant mode, after 24 hours) and 2 o opti which 000 re 000000007600000001008900000009ю00000000zhae (with sch " o 2.3 (zotovoetYa silicone 0 vrozninniyu 000 b,Fumaato000060000000onevinmo 2

LLC Mn

Notes:-

F

- absorption, (ge) (2-I3-(1,1-diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol)fesoterodine, «

According to this, the content of the salt component of the compound of the general formula | should be minimal

With" possible. Usually, the proportion of the salt of the compound of the general formula I introduced into the polymer matrix should be less than 20% by weight, preferably less than 10.5 or 3% by weight. 95, especially better less than 1 wt. 95, from the entire mass of the active substance used.

According to the invention, the compounds of the general formula I are more than 9095, better than 9595, especially better than 9995, presented in the form of highly pure optical isomers (enantiomers) with - (K)-configuration. This means that the proportion of compounds with the (5)-configuration is less than 1095, preferably less than 395, especially preferably less than 195. In one of the best embodiments of the invention, the polymer matrix has a specific gravity in the range from 30 to 50 ZbOg/m2 and contains from 50 to 95 wt.95 of a polymer, preferably a polymer that is capable of self-adhesive (contact adhesive), and from 5 to 40 wt. of a compound of the general formula I (in each case, in terms of the total mass of the polymer matrix).

In a particularly preferred embodiment of the invention, the device proposed therein differs in that it (a) has a maximum surface area of 50 cm, (b) has a polymer layer that is capable of self-adhesive, which

GF) (61) has a specific mass from 30 to 100/m2, t (62) contains from 50 to 95 wt.95 of contact adhesive, (63) contains from 5 to 40 wt.90 of compounds of the general formula | in terms of the total mass of the polymer bo layer, and especially preferably (c) is able to release the compound of the general formula I for at least 24 hours with a rate of its penetration through the human skin in a steady state, which is at least 4 μg/cm/h.

In another preferred embodiment of the invention, the medicinal product proposed therein contains a compound of the general formula I, in which K is C 1-Salkyl, selected primarily from the group that includes methyl, ethyl, 65 1-propyl, isopropyl, 1-butyl, 2 -butyl, tert-butyl, isobutane, pentyl and hexyl.

In the most preferred embodiment of the invention, the polymer matrix of the medicinal product for transdermal use contains (KO-2-I3-(1,1-diisopropylamino)-1-phenylpropyl/|-4-(hydroxymethyl)phenylisobutyrate (fesoterodine) as an active ingredient.

According to the present invention, the term "C-Svalkil" refers to a hydrocarbon group containing from 1

UP TO 6 C-atoms with a straight or branched chain.

The term "C 3-C-ocycloalkyl" refers to a cyclic hydrocarbon group containing from 3 to 10 carbon atoms.

According to the invention, the term "polymer" also includes copolymers.

The term "polymer matrix" (or simply "matrix") refers to a polymer-containing layer, a polymer-containing interlayer or a polymer-containing mass. If the polymer matrix is self-adhesive, it is also called an "adhesive matrix".

According to the invention, the term "total mass of the polymer matrix" refers to the mass of the polymer matrix, including the mass of the active substance introduced into it and possible auxiliary substances.

The device proposed in the invention refers to a transdermal device/transdermal 7/5 Pharmaceutical form of the matrix type, usually flat, that is, the active substance is present in the form introduced (dissolved or dispersed) in a polymer layer or polymer mass.

The device proposed in the invention preferably contains a monolithic adhesive matrix into which the active substance is introduced.

An example of a typical structure of a monolithic transdermal device (transdermal therapeutic 2nd system, TT) is shown in Fig.4. The device schematically shown in this drawing consists of an adhesive matrix (1) that contains an active substance, an inert to the components of the adhesive matrix and a back layer (2) impermeable to them, which, after applying the patch to the patient's skin, is located on the side of the patch facing away from the skin. and also from the layer (3), which protects the adhesive matrix during storage and is removed before use. high school

According to the invention, the surface area of the transdermal device proposed in the invention is a maximum of 50 cm2, preferably a maximum of 40 cm?. Patches with a size from 5 to 35 cm-, most preferably from 10 to 33 cm-7 are especially preferable.

A polymer matrix that contains a contact adhesive and an active substance, for example, an adhesive matrix usually has a thickness of 30 to 30 µm, preferably 40 to 200 µm, and an average specific gravity of 30 to Zbog/m2, preferably 40 to 200 g/m7. "Mr

According to the invention, the concentration of the active substance in the polymer matrix, preferably the adhesive matrix, which is part of the device/medicinal agent, designed for use for, for example, 2-3 days, (F) is from 5 to 4Omas.9o, preferably from 7 to ZOmas.9o, especially better from 8 to 20mas.95, in terms of "- the total mass of the adhesive matrix. If it is necessary to obtain a medicinal product designed for the introduction into the body of a compound of the general formula I for 7 days, the active substance is used in relatively higher 89 concentrations, exceeding 15% by weight, which is preferably from 20 to 4% by weight.

Accordingly, the concentration of the active substance in the polymer layer, for example, in the adhesive matrix, can be in the range from 0.15 to 12 mg/cm?. It is desirable that the concentration of the active substance in the polymer layer was from 0.25 to 7.5 mg/cm2, especially better from 0.32 to Amg/cm2. In devices designed for 70 uses within 7 days, the concentration of the active substance in the polymer layer should preferably be no less than 2mg/cm7. :z» According to one of the variants of the invention, the free base of the general formula | present in the corresponding polymer matrix in a concentration at which it is supersaturated with the active substance. Such oversaturation of the polymer matrix with the active substance can lead to the formation of so-called microreservoirs, which are present in the matrix, primarily in a hydrophobic matrix, for example, of the silicone type, in the form of droplets. In this case, the microreservoirs containing the active substance should preferably have the most uniform size distribution, and their average size should not exceed 5095 of the thickness of the matrix layer. It is possible to ensure compliance with this condition due to intensive homogenization of the matrix in the process of its preparation, as a result of which the average size of the droplets distributed in it, especially better, does not exceed ZOμm.

In another embodiment of the invention, the active substance is present in the matrix, for example, in the acrylate matrix, in such a concentration that it is completely dissolved in it.

The free bases of the general formula I, which are used to manufacture the devices proposed in the invention, can in principle be obtained by the method described in MO 99/584781I.

For this purpose, (K)-2-(3-isopropylamino-1-phenylpropyl)-4-hydroxymethylphenol is subjected to interaction in alkaline

HF) conditions with an acid chloride suitable for this purpose, for example, isobutyric acid chloride. It should be noted, however, that the indicated reaction allows obtaining the required main product (B) in a yield that is only from about 90 to a maximum of about 9495. The product usually contains from 6 to 1095 impurities, which are the starting substance (A), as well as unwanted reaction products in the form of the corresponding complex diester (C), complex monoester (0) of the 4-hydroxy group (see Fig. 1) and products that are formed as a result of polymerization.

However, the purity of the medicinal substance for the possibility of its use in pharmaceutical preparations must usually exceed 97% by weight. 65 In accordance with the invention, it was unexpectedly established that obtaining a free base of the general formula (given below) with a purity exceeding, as a rule, 97% by weight, preferably exceeding 98% by weight, preferably exceeding 98.5% by weight, which is the most preferably greater than 9Omas.9o, and with a good yield of more than 8Omol.U", usually more than 9Omol.Uo, possibly by releasing it from a high-purity crystalline salt with a suitable reagent.

According to the invention, it was established that obtaining the free base of the general formula I with a purity exceeding, as a rule, 97mass.9o, preferably exceeding 98mass.9o, especially preferably exceeding 98.5mass.9o, most preferably exceeding 9Omas.bo , and with a good yield, which is usually more than 9Omol.bo, possibly by releasing it from a highly pure crystalline salt using a reagent suitable for this purpose. 70 Under the term "high purity" according to the invention is meant a degree of purity exceeding at least 97mas.9o, preferably exceeding 98mas.9o, especially preferably exceeding 98.5mas.9o, most preferably exceeding 9OUmas.9o. The degree of purity is determined using the methods discussed below in the relevant section of this description.

Proposed in the invention are highly pure bases of the general formula | can be obtained by releasing them from 7/5 of high-purity crystalline salts of the general formula HER

And I

20 no f o ok sch 25 KZ I, o fi z

M (ge) 30 marks "I

Ah x "-- in which A and K have the values indicated above, and X- means the residue of the corresponding physiologically compatible 35 acid and in which the symbol "" (asterisk) C-atom can be in the (K)-configuration, so (5 )-configuration or in a mixed configuration.

At the same time, the acidic residue X- can be primarily an anion of one of the acids from the group, which includes hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic 70 acid, succinic acid, OI-malic acid, I-(-)U-malic acid, O-(n)-malic acid, Oi-tartaric acid, I-(k)-tartaric acid, Y-(---tartaric acid, citric acid, I-aspartic acid, I1-(-)-ascorbic acid, Y-(y)-glucoronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid acid (pyrolysic acid), benzoic acid, 4-hydroxybenzoic acid, salicylic acid, vanillic acid, 4-tihydroxycinnamic acid, gallic acid, hippuric acid (M-benzoylglycine), aceturic acid (M-acetylglycine), phloretinic acid (3-( 4-hydroxyphenyl)propionic acid), phthalic acid, methanesulfonic acid and orotic acid tu, while such anions of acids as hydrofumarate and as hydrochloride are especially preferred.

From the specified high-purity compound of the general formula I, the corresponding high-purity free bases are also released by admixing reagents suitable for these purposes ("releasing reagents"). t» 50 As an example of such release reagents, one can name alkaline compounds from the group that includes - hydroxides, carbonates and bicarbonates of alkaline, alkaline earth metals and ammonium, so - amines, polyamines and basic polyamino acids, which can be presented both in dissolved form and in the form fixed on the appropriate carriers, and - basic ions, preferably weakly alkaline compounds with an acidity index (pKv) of 8-11.

HF) The most preferred release agent is alkali metal, alkaline earth metal or ammonium bicarbonate, sodium bicarbonate being particularly preferred. In one of the best variants of implementing the method discussed above, first, the salt of formula II is dissolved in water and mixed with the main release reagent, for example, with bicarbonate. Then the mixture is extracted with a suitable solvent by shaking and the organic phase is concentrated to obtain a residue of the highly pure base of formula I in the form of a viscous oil. This variant of the implementation of the method is considered in more detail in example B.

Dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, ethyl methyl ketone, as well as toluene are primarily suitable solvents for use in this method, especially dichloromethane.

In another embodiment of the method discussed above, first, the highly pure salt of formula II is dissolved in a suitable solvent, after which it is passed through a medium containing, for example, an ionite fixed on its surface. In this case, a highly pure base of the general formula I is contained in the eluate.

To obtain (K)-2-I3-(1,1-isopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenylisobutyrate in the form of a highly pure free base, it is particularly desirable to use as the starting compound of formula I! hydrofumarate (KO-2-I3-(1,1-diisopropylammonium)-1-phenylpropyl/|-4-(hydroxymethyl)phenylisobutyrate.

The method of obtaining highly pure salts of formula II is known from (MYO 01/35957). For this purpose, first a solution of 2-I3-(1,1-isopropylamino)-1-phenylpropyl|-4-(hydroxymethyl)uphenol is subjected to interaction in an alkaline solution with 70 chloride of the corresponding acid, for example, with chloride of isobutyric acid. Then the base obtained in this way with a low degree of purity is mixed with an acid, for example, with fumaric acid, when heated. The resulting salt of general formula II can be crystallized from appropriate solvents.

The obtained crystals are again dissolved and recrystallized. If necessary, this process can be repeated several times until the compound of formula II is obtained as a result with the required degree of purity. From such salts /5, the highly pure base of formula I is released by the method described above.

Table 2 presents the results of purification of fesoterodine in the form of a base using the method proposed in the invention.

Table 2

Stages of method 2) Purity of compound B or E (95) 1. Chemical synthesis of base B from compound A 94.37 2. Preparation of salt E from base B obtained in stage 1 92.58 3. Recrystallization of salt E obtained in stage 2 99 ,32 4. Highly pure base B, isolated from the salt E 99.14 se obtained at stage C of a) compounds A, B, C, E: K means isopropyl, see Fig.1.

The method described above allows for the first time to effectively obtain free bases of the general formula I in a highly pure form, thereby providing for the first time the opportunity to apply highly pure bases of the general formula

It is for the manufacture of devices proposed in the invention, intended for controlled transdermal introduction of these active substances into the body. b

According to this, the preferred object of the invention is a device for transdermal introduction into the body of the compound of the formula | Thursday

MA co

Ff re - : Y it Z z co - M (se) АХ их 50 s in which A is hydrogen or deuterium, and K is a group selected from C-Salkyl, C3-Siocycloalkyl and phenyl, each of which can be substituted by C.--Salkoxy group, fluorine, chlorine, bromine, iodine, nitro group, amino group, hydroxy group, oxo group, mercapto group, or deuterium, and in which the symbol "" (asterisk) C atom is in the (K)-configuration, which differs by the fact that, during its production, the compound of the general formula I in the form of a free base with a degree of purity above 97% by weight, preferably above 9% by weight, especially (F. preferably above 98.5% by weight, most preferably above 39% by weight, 9% by weight) is introduced into the polymer layer, preferably in a polymer matrix capable of self-adhesive (adhesive matrix).

A particularly preferred object of this invention is a flat-shaped device for transdermal 60 administration of compounds of formula b5

А z no Ф о о вю Ж І, in which A means hydrogen or deuterium, and K represents a group selected from C 4-Salkyl, C 3-Siocycloalkyl and phenyl, each of which can be substituted by a C--C salkoxy group, fluorine , chlorine, bromine, iodine, nitro, amino, hydroxy, oxo, mercapto, or deuterium, and in which the "" (asterisk) C atom is in the (K)-configuration, which is distinguished by the fact that it (a) has surface area maximum cm, (b) has a polymer matrix that is capable of self-adhesive, that c (61) has a specific mass from 30 to Зbbg/m7 and o (62) contains from 50 to 95 wt.95 of contact adhesive, (c) contains dissolved or dispersed in the polymer matrix (b), which is capable of self-adhesive, the compound of the general formula I, which (b1) is present in the polymer matrix in a concentration from 5 to 4Omas.95 in terms of its total weight, co (82) is introduced into the specified polymer layer preferably in the form of a free base with a salt content of less than "g 1Omas.9o, as well as (c3) with a degree of purity preferably more than 97oMas.95, better more than 9Vmas.956, especially better more than F) 98.5mas.95, most better more than 9U9mas.9b5. "-

In a particularly preferred version, the compound introduced into the polymer layer is (B)-2-I3-(1,1-isopropylamino)-1-phenylpropyl|-4-(hydroxymethyl)phenylisobutyrate (fesoterodine) in the form of (he) highly pure free base.

A wide variety of polymers, known for their use in the technology of plaster production, can be used to obtain the polymer layer, while it is desirable to use polymers as contact adhesives that have properties that are discussed in more detail below.

In general, the penetration of a certain active substance through human skin largely depends on the features of the matrix into which it is introduced. In the case under consideration, all the matrices that are capable of self-adhesive that "" were used, contrary to expectations, ensured in the experiments that the active substance " through the skin of the mammal at a high speed (Fig. 3, Table 1). This is due to the extremely high ability of free bases of the general formula I, and primarily fesoterodine, to penetrate the skin.

To begin with, it is assumed that the effective average daily dose of the active substance for the patient, which is transported through the skin, correspondingly to the active metabolite, which is - (К)-2-И3-(1,1-isopropylamino)-1-phenylpropyl|-4- (hydroxymethyl)uphenol, should be from 0.5 to 2Omg, usually at least 3mg, for example, from 3 to 20Omg, preferably from 3 to 15mg, especially preferably from 4 to 12mg. However, in (Ce) in some cases, it may be sufficient to enter the active substance into the body in a smaller daily dose, 20 of which is from 0.5 to Zmg, or, on the contrary, it may be necessary to enter the active substance into the body in a larger daily dose, exceeding 20 mg . 12; TTS, in which (K)-fesoterodine in the form of a highly pure base is introduced in an amount of 15 wt.bo into a corresponding 5X5- or EVA-type adhesive matrix, provide in the experiments of ip mygo such a rate of penetration of the active substance through the human skin that with the corresponding surface area of the skin , which is covered, which is from 5 to 22 50 cm, allows you to determine the therapeutically necessary daily dose, as presented below in Table 3.

Bsm? 10cm2 20cm2 ZOcm? 40 cm2 Bosm2 » tan and Piy Pn Piy Bozhii biy acrylic (Oshtoivk vt-4287) | t 33 16617 lo | 33 | you would5

According to the experimentally obtained data, the medicinal products proposed in the invention, the matrices of which contained fesoterodine in the form of a free base, unexpectedly ensured the transdermal penetration of this active substance through the human skin at a rate in a steady state of more than Зб0Омkg/cm"/day, i.e. more than 1Змkg/ cm2/hour, for at least 48 hours (Fig. 2).

At the same time, the rate of penetration of the active substance through human skin from the polymer matrices proposed in the invention unexpectedly significantly exceeded the rate of penetration of the active substance through human skin from a free solution known from (MUO 99/58478).

The matrices proposed in the invention, due to the constantly high rate of penetration of the active substance through the skin provided by them, unexpectedly make it possible to manufacture a device for the controlled transdermal 70 introduction into the body of compounds of the general formula I, primarily (KO-2-I3-(1,1-diisopropylamino)-1-phenylpropyl /|-4-(hydroxymethyl)phenylisobutyrate (fesoterodine in the form of a free base) within the entire range of therapeutically necessary dosages, which are from 0.5 to 2Omg/day, with a constant rate of penetration for at least 24 hours without a significant increase in its total surface area over 50cm,

Accordingly, another object of this invention is a medicinal product for transdermal introduction into the body of a compound of general formula I in the form of a free base, primarily (KO-2-I3-(1,1-diisopropylamino)-1-phenylpropyl/|-4 -(hydroxymethyl)phenylisobutyrate (fesoterodine in the form of a free base), for at least 24 hours, preferably at least 48 hours, with a constant rate of penetration of this active substance through the skin, which is more than 125 mcg/h, better from 125 to 850 mcg/h, especially better from 125 up to 65 Ohmkg/h, most preferably from 150 to 50 Ohmkg/h.

Another object of this invention is a drug for continuous transdermal administration of a compound of general formula I in the form of a free base, primarily (KO-2-I3-(1,1-diisopropylamino)-1-phenylpropyl/|-4-(hydroxymethyl ) of phenylisobutyrate (fesoterodine in the form of a free base), for at least 24 hours, preferably at least 48 hours, with a rate of penetration of the active substance into the CM in a steady state of more than 4 μg/cm"/h, better more than bmkg/cm"/h, especially better more than 8, 10 or Ge) 12μg/cm/h, while the rate of penetration is determined in an IP mygo experiment on a model of human skin using the Tapio method described in example 3.2.

The model used in accordance with the invention, the determination of the rate of penetration of the active substance through the skin, proposed by Tapofo, turned out to be the most successful model, in which the measured ip migo speed of penetration through the skin correlates to the maximum degree with similar indicators of the speed of ip MMo /-«f and indicators of the level of the active substance in plasma obtained during numerous clinical studies of various amine-containing active substances. (22

The measured daily rate of penetration, which is provided by the devices proposed in the invention, "corresponds, according to the results of clinical studies, to the optimal effective dose for most patients

Zo (KO-2-I3-(1,1-diisopropylamino)-1-phenylpropyl/|-4-(hydroxymethyl)phenylisobutyrate (fesoterodine) with its oral intake (approximately from 4 to 12 mg per day), in which therapeutically necessary the plasma level of its metabolite, i.e. (K)-2-I3-(1,1-diisopropylamino)-1-phenylpropyl|-4-(hydroxymethyl)phenol, is from 1 to 15 ng/ml, preferably from 2 to 12 ng/ml , especially better from 3 to 1 Ong/ml.

According to this, another object of the invention is a medicine for transdermal introduction into the body of compounds of the general formula I, primarily o, c (KO-2-I3-(1,1-diisopropylamino)-1-phenylpropyl/|-4- (hydroxymethyl)phenylisobutyrate (fesoterodine in the form

From" the free base), with the speed of its penetration through the skin, at which the plasma concentration of its metabolite, which is (К)-2-И3-(1,1-isopropylamino)-1-phenylpropyl|-4-(hydroxymethyl) phenol is maintained for at least 24 hours, preferably at least 6 hours, at a constant level of 1 to 15 ng/ml, preferably 2 to 12 ng/ml, especially preferably 3 to 1 ng/ml. The term "steady mode" according to the present invention refers to the rate of penetration of the active substance through the skin, which is established after the completion of the initial delay phase after the initial application of the device proposed in the invention to the skin. The term "permeation rate in a steady state" refers to the rate of penetration of the active substance through the skin, which is established after the completion of the initial delay phase.

Under the expression "constant rate of penetration" according to the present invention, we mean the rate of penetration in a steady state, at which the compound of the general formula I is transported through the human skin with some average speed, which is characterized by a determined, internal variability of CM in time, which does not exceed 30905 , preferably does not exceed 2095 or even 1095, and which is calculated according to equation 29 slu-(sa; xIx100o calculations see in "Ragateyegtg iog Sotrapetepi-iiteee RNagtasokipeiisv", edited by (F) Same, in Zpakeg Mepad, Aaspep , 1999, p.112). At the same time, the daily dose is injected into the body with an average

Ф by the rate of penetration, which is calculated by dividing the daily dose by 24h (and which is expressed as mg/h), with the value of the variability of CM, which is equal to 3095. It is obvious to a specialist in this field that a constant rate of penetration is established only after the completion of the initial stage of "inflow" of the active substance to the skin (delay phase) after the initial application of the device to the skin. Therefore, when calculating the constant rate of penetration, the delay phase is not taken into account.

Under the expression "speed of penetration through human skin" according to the invention is meant, unless otherwise specified, the speed measured by ip migo on a model of human skin according to the Tapo|o method, which is described in example c5 32.

The term "constant plasma level" or "constant plasma concentration" according to the invention means that during at least 8095, preferably at least 8595, especially preferably at least 9095, the time during which the active substance enters the body from the medicinal product proposed in the invention and which counted from the moment of completion of the initial delay phase after the initial application of the medicinal product proposed in the invention to the skin, there is a certain level of the active substance in the patient's plasma.

The polymer layer of the devices proposed in the invention generally contains from 50 to 95wt.9o, preferably from 70 to 30wt.9o, of polymer, which is preferably activated upon short-term pressing of the polymer (contact adhesive).

As the basis of a polymer layer capable of self-adhesive, in principle, contact adhesives known from their use in the technology of patch production can be used, for example, organosilicon (silicone) adhesives, adhesives based on copolymers of ethylene with vinyl acetate (EVA adhesives), adhesives based on block copolymers of styrene (5X5 adhesives), acrylate adhesives, polyurethane adhesives, vinyl acetate adhesives, as well as adhesive rubbers, for example, polyisobutylene, polybutadiene, neoprene or polyisoprene, as well as appropriate mixtures of these adhesives.

According to this, another object of the invention is a device for transdermal introduction into the body of 7/5 bpoluk of the formula y kho no f o ov 5 ZHI I, sch vve I

M co " Z "I (2) in which A means hydrogen or deuterium, and K is a group selected from C 4-Salkyl, C 3-Siocycloalkyl and p-phenyl, each of which can be substituted by a C-S-alkyloxy group, fluorine, chlorine, bromine, iodine, nitro group, amino group, hydroxy group, oxo group, mercapto group or deuterium, and in which the C-atom marked with the symbol "" co (asterisk) is in the (K)-configuration, which differs in that the compound of the general formula preferably in the form of a free base introduced into a polymer layer that is capable of self-adhesive, containing at least one contact adhesive selected from the group that includes silicone adhesives, adhesives based on copolymers of ethylene with vinyl acetate (EVA adhesives), adhesives based on block copolymers of styrene ( 5X5-adhesives), acrylate adhesives, 70 polyurethane adhesives, vinyl acetate adhesives, adhesive rubbers, for example, polyisobutylene, polybutadiene, neoprene or polyisoprene, and appropriate mixtures of these adhesives. z Polymer layers that contain an active substance can, in principle, be obtained by the method , os based on the use of a solvent, or a method based on the use of a melt.

When obtaining a polymer layer by a method based on the use of solvents, each of the components, which are the active substance and the polymer, as well as other auxiliary substances used in some cases, are separately dissolved in the appropriate solvents and then the resulting solutions are mixed between by myself After that, the resulting mixture is distributed in an even layer over the surface of the film and when heated, the solvents evaporate.

When obtaining a polymer layer by a method based on the application of a melt, polymers, as well as auxiliary substances, which are used in some cases, are melted by heating without the use of 50 solvents, mixed and the obtained melt is distributed in an even layer on the surface of the film. Usually, the active substance is injected directly into the liquid melt. For processing by the method based on the use of a melt, those polymers are suitable first of all, which, at processing temperatures not exceeding 2002С, have sufficient fluidity, that is, their dynamic viscosity preferably does not exceed 100 Pa.s. Dynamic viscosity can be determined according to the method described in (05 5328696).

According to the invention, it was unexpectedly found that compounds of the general formula I, first of all

GF) fesoterodine, at processing temperatures that are characteristic of the method based on the application of the melt, and which reach 2002С, remain stable.

The most suitable for use as contact adhesives are known polymers of the acrylate type, ХХ5 type, 60 EVA type, as well as silicone type, primarily capable of forming a melt mixture of silicone with a plasticizer. These contact adhesives have sufficient stickiness to human skin and provide a high rate of penetration of highly pure bases of the general formula I, primarily fesoterodine, through the skin. Such glues are well tolerated by the skin and are suitable for use in pharmaceutical purposes. The properties and preparation of such better contact adhesives are discussed in more detail below. 65 Silicone adhesives

The best contact silicone adhesives are amino-resistant polyorganosiloxane adhesives that are activated by short-term pressure (contact).

Contact silicone adhesives are in most cases polydimethylsiloxanes, however, in principle, other organic residues, such as ethyl or phenyl groups, may be present instead of metal groups in such adhesives. Such amino-resistant contact silicone adhesives usually differ in that they do not contain free silanol functional groups at all or contain only a small amount of them, since the z-OH groups have undergone alkylation. Such adhesives are described in (EP 180377). Especially the best glues of this type include condensates or mixtures of silicone resins and polyorganosiloxanes, which are described, for example, in (05 KE 35474). 70 Suitable glues are produced, for example, by Yuomzh/Sogpipud in the form of so-called bio-ACP glues (ACP means "activated by short-term pressing"). Mixtures of bio-ACP glues 207-4301 and 37-4201 are especially suitable for this, primarily in their ratio in the range from 40:60 to 60:40.

Patches-matrixes based on silicone adhesives are mainly made by methods based on the use of solvents. For this purpose, at the first stage, a 7/5 solution in an organic solvent or a mixture of solvents is prepared from contact adhesives and the active substance. At the second stage, the solution is distributed in an even layer and laminated, after which the solvent is removed. This method is described, for example, in MO 99/498521.

An alternative method, which does not use organic solvents, is based on the application of melt glue. When implementing this method, the polymer, respectively, the contact adhesive, is melted by heating to a temperature in the range from 70 to 2002C, preferably from 90 to 1602C, most preferably from 100 to 1502C, first the active substance is introduced into the homogenized melt of the matrix. After a short homogenization, the adhesive matrix, which contains the active substance, is cooled again, as a result of which the active substance is exposed to thermal stress for usually less than 5 minutes, and if necessary, for less than 4, 3, 2 and even less than 1 minute. As a result, the active substance is introduced into the hardened polymer melt. During this process, the active substance is maximally protected from the unwanted influence of external factors (light, oxygen). with

The advantage of this method over the method based on the use of solvents is that highly pure bases of the general formula | are not exposed to solvents, and they can be immediately introduced into i) the glue melt, where after a short homogenization, their stabilization takes place in the polymer matrix, which is cooled. A similar method, based on the use of a melt, is preferably carried out in an extruder, for example, in a twin-worm extruder, as described in (MUO 99/48493). with

Silicone adhesives at the processing temperatures indicated above usually have a too viscous consistency, that is, their dynamic viscosity exceeds 150 Pa.s. The patent literature describes various methods of reducing the viscosity of silicone adhesives by mixing with them suitable for this purpose impurities b (plasticizers) and thus giving them the ability to form a melt. Examples of such plasticizers for silicones include glycerin monolaurate or lauryl acetate described in (EP 835136), waxes of the formula (87

K-F(0)-OK, described in (EP 360467), alkylmethylsiloxane waxes, described in (EP 524775), siloxated (Fu) polyester waxes, described in (EP 6634311, or organic waxes, described in (05 KE 36754).

Usually, plasticizers are added to silicone glue in an amount from 1 to ZOmas.bo in terms of the total mass of the adhesive mixture capable of forming a melt. The best plasticizers are organic waxes, which are described in (05 KE 36764), for example, ozokerite, ceresine, paraffin, candelilla wax, carnauba wax, beeswax or mixtures of these waxes, the most preferable of which are ozokerite and ceresine. - c Pre-prepared, melt-forming contact silicone adhesives, in particular mixtures of such and silicone adhesives with ceresin or ozokerite, can be purchased from Yuom/Sogpipo, pcs. Michigan. Due to the addition of ceresin to the contact silicone adhesive in the amount of TOmas.9o, it was possible, for example, to reduce the dynamic viscosity of the resulting adhesive mixture at the processing temperature of 1502 from a value exceeding 200 Pa.s to a value below 50 Pa.s. a mixture that contains contact silicone glue can be (se) successfully processed by a method based on the use of a melt, in the temperature range from 70 to 2002C, - primarily from 100 to 1502b.

According to the invention, it was unexpectedly found that melt-forming contact silicone (se) adhesives can be effectively used for transdermal administration of compounds of the general formula I. Another object of the invention according to this is a device for transdermal administration of compounds of the formula II. »)

Ф) ko 60 b5 y kno f o ov y Х І, in which A means hydrogen or deuterium, and K is a group selected from C-Salkyl, C3-Siocycloalkyl and 20 phenyl, each of which can be substituted by C .--by a salkoxy group, fluorine, chlorine, bromine, iodine, nitro group, amino group, hydroxy group, oxo group, mercapto group or deuterium, and in which the symbol "" (asterisk) C-atom is in the (K)-configuration, which is distinguished by that the compound of the general formula is introduced into a polymer layer capable of self-adhesive (adhesive matrix), which includes amino-resistant silicone. cm 25 Compound of the general formula | preferably introduced into the silicon matrix in the form of a free base, especially He) preferably in the form of a highly pure free base.

In the best version, the silicone-based matrix proposed in the invention contains fesoterodine as an active substance.

In a particularly preferred embodiment of the invention, the basis of the adhesive matrix is a melt-forming mixture of silicone-based contact adhesive and at least one plasticizer, primarily an organic wax, such as ozokerite.

Another object of the invention is intended for transdermal administration of the compound of the general formula | Ф a medicinal product that has an adhesive matrix, which contains part a) from 50 to 9Omas.9o of contact adhesive in the form of a mixture of 35 1) 70-99o by mass of amino-resistant silicone glue and co 2) 1-3Omas.9o, preferably 3 -15wt.9o, an acceptable plasticizer, preferably an organic wax, especially preferably selected from the group that includes ozokerite, ceresine, paraffin, candelilla wax, carnauba wax, beeswax and mixtures of these waxes, especially preferably ozokerite and ceresine, and "b ) from 1 to 4Omas.9o of the compound of the general formula I introduced into it mainly in the form of a free base, 70 most preferably in the form of a highly pure free base. in c One of the variants of implementation of the invention relates to a device for transdermal introduction into the body "from a compound of formula I, which is dissolved or dispersed in a polymer layer that is capable of self-adhesive, provided that if the polymer layer that is capable of self-adhesive consists of silicones in which fesoterodine in the form of a free base is dispersed in them in the form of microreservoirs, then such silicones (a) are presented in a mixture with other polymers not on a silicone basis or (b) are presented in a mixture with plasticizers, the dynamic viscosity of which at a temperature of 200 "C, is - less than 100 Pa.s, preferably less than 80 Pa.s "so Figure 3 shows the graphs of the rate of penetration of the active substance through the skin of a mouse, built on the basis of 5p data obtained by migo when applying a patch made on the basis of silicone glue based on

FT" using its melt by the method that contained ozokerite as a plasticizer for the adhesive matrix, as well as fesoterodin introduced into it in the form of a highly pure free base. EVA adhesives (o Contact EVA adhesives are melt-forming contact adhesives based on copolymers of ethylene with vinyl acetate ("EVA adhesives"). Such EVA adhesives are described, in particular, in the patent (05 4144317). EVA adhesives differ with good adhesive properties, ease of preparation and processing, as well as good skin tolerance.EVA glues can be purchased, for example, from Weagdom Adatz (133/BA).

GF) Regarding the processing of the named glues by a method based on the use of a melt, everything said above is true in principle in relation to silicone glues, except that plasticizers usually do not need to be added to EVA glues. According to this, another object of the invention is a device for transdermal administration into the body of a compound of the formula b5 and kno f o ov y Z I, in which A represents hydrogen or deuterium, and K represents a group selected from C --Svalkilu . The C-atom is in the (K)-configuration, which is characterized by the fact that the compound of the general formula is introduced into a self-adhesive polymer layer (adhesive matrix), which includes an EVA-type contact adhesive. with 25 o. . and

The compound of the formula | it is better to introduce into the EVA matrix in the form of a free base, especially preferably in the form of a highly pure free base.

In the best version, the EVA-based matrix proposed in the invention contains fesoterodine as an active substance.

In a particularly preferred embodiment of the invention, the adhesive matrix based on EVA glue is obtained by a method based on the use of a melt. со 3о Fig. 2 and 3 show the graphs of the rate of penetration of the active substance through human skin, respectively, through the skin of a mouse, built on the basis of data obtained by ip migo when applying a patch that is made on the basis of EVA glue by a method based on its use melt, and which contains fesoterodin introduced into the adhesive matrix in the form of a highly pure free base. h-

Contact ХЗ-ADHESIVES 35 Contact 5X5-adhesives can be processed both by the method based on the use of solvents and by the method based on the use of melt. According to the invention, the term "contact Х5-adhesives" (hereinafter 5Х5-adhesives) refers to adhesives based on styrene block copolymers, the macromolecules of which carry non-elastomeric styrene blocks at the ends, and elastomeric blocks in the middle. Elastomer blocks can be, for example, polyethylene butylene, polyethylene propylene, polybutadiene, polyisobutylene or polyisopropene. 70 Suitable 5X5 adhesives are described, in particular, in (patent О5 5559165 or 05 55275361, and they are characterized by good adhesion properties, ease of preparation and processing, as well as good skin tolerance. Contact 5X5 adhesives are commercially available, for example, under the name of Yugo Tak 378-3500, a product of the company Maiyopa!

Spetisai!| or they can be obtained independently in a worm melter when making plasters that contain the active substance.

For this purpose, for example, an appropriate amount (at least of the components listed below) of block copolymer with styrene (for example, Kgaip 5X1657 or Kgap 0-1107С2O of the ZnNei company) with aliratic and/or aromatic resin (for example, Kedaije K1090, Kedaije K1010 or Kedaije K1100 of the company Keuzeg MaskKau) and oil (for example, type Opaipa 933 or Opaipa 941 of the company 5pei) are fed from separate dosing devices into the worm o melter, where they are mixed with each other and melted. At the last stage, the active substance is dosed into the t" 50 contact adhesive obtained in this way in a worm melter and the resulting mass is applied in an even layer on the films. Polymer, resin and oil are usually used in a mass ratio between them, which is

For example, 100:120:20 or 100:200:50. By varying this quantitative ratio between the specified components, the properties of Х5-Glue can be adjusted accordingly with the necessary properties of TTS (stickiness, minimum fluidity in the cold state, duration of stickiness storage, release profile of the active substance, etc.). 59 Another object of the invention according to this is a device for transdermal introduction into the body

F! compounds of the formula ко 60 b5 и kno f o ov y Ж I, in which A is hydrogen or deuterium, and K is a group selected from C -Salkyl, C3-Siocycloalkyl and 20 phenyl, each of which can be substituted by C .--by a salkoxy group, fluorine, chlorine, bromine, iodine, nitro group, amino group, hydroxy group, oxo group, mercapto group or deuterium, and in which the symbol "" (asterisk) C-atom is in the (K)-configuration, which is distinguished by that the compound of the general formula is introduced into a polymer layer capable of self-adhesive (adhesive matrix), which includes a contact adhesive based on 5X5. with 25 o. . and

The compound of the formula | it is better to introduce into the 5X5 matrix in the form of a free base, especially preferably in the form of a highly pure free base.

In a particularly preferred version, fesoterodine, most preferably fesoterodine in the form of a highly pure free base, is introduced into the ХХ5-based matrix proposed in the invention as an active substance.

In another especially better embodiment of the invention, the adhesive matrix based on ХХ5 is obtained by a method based on the use of a melt. WHAT

Figures 2 and 3 show the graphs of the rate of penetration of the active substance through human skin, respectively through the skin of a mouse, built on the basis of data obtained by applying a patch made on the basis of 5ZX5-glue by a method that is based on the use of its melt and which contains fesoterodin -chpr introduced into it in the form of a highly pure free base. 35 Since 5X5 adhesives tend to oxidize, it is desirable to add antioxidants to adhesive matrices based on them. As an example of an antioxidant suitable for this purpose, IgdaapokhF (product of the company

SIVA).

Acrylate glues «

Polyacrylates are obtained by radical polymerization of derivatives of (meth)acrylic acid, while other 70 monomers can also be used as other compounds, such as, for example, vinyl acetate. It should be noted that in c the term "polyacrylate" used in this case includes polymers that contain units based on acrylic acid and/or methacrylic acid, as well as their copolymers and mixtures.

By selecting the appropriate monomers, the contact adhesives obtained from them can in principle be given special properties, i.e. provide the optimal ability to dissolve the active substance, the necessary mobility of the active substance in the matrix, and also ensure the necessary speed of its transportation through the skin. It should be noted that the speed of transportation of the active substance through the skin is significantly limited by its distribution coefficient and its absorption through the skin.

Polyacrylate-type glue activated by short-term pressing (contact) can be a homopolymer and/or copolymer of at least one derivative of acrylic acid and/or methacrylic acid in the form of a solution in an organic solvent. Contact adhesive of the polyacrylate type can be cross-linked or non-cross-linkable. The cross-linking agent binds the polymer chains with the help of reactive CO groups with an increase as a result of the cohesion of the contact adhesive.

The polyacrylate-type polymeric contact adhesive preferably consists of at least monomers selected from the group consisting of acrylic acid, acrylamide, hexyl acrylate, 2-ethylhexyl acrylate, hydroxyethyl acrylate, 59 octyl acrylate, butyl acrylate, methyl acrylate, glycidyl acrylate, methacrylic acid, methacrylamide,

HF) hexyl methacrylate, 2-ethylhexylamide acrylate, octyl methacrylate, methyl methacrylate, glycidyl methacrylate, vinyl acetate, vinyl pyrrolidone and allyl acrylate. The best contact polymer adhesives of the acrylate type include crosslinkable contact adhesives obtained by polymerization of monomers in the following combinations: 60 2-ethylhexyl acrylate/M-butyl acrylate/butyl acrylate/acrylic acid, 2-ethyl hexyl acrylate/M-butyl acrylate/vinyl acetate /acrylic acid, 2-ethylhexyl acrylate/vinyl acetate/acrylic acid, 2-ethylhexyl acrylate/vinyl acetate/allyl acrylate, 2-ethylhexyl acrylate/vinyl acetate/divinylbenzene/acrylic acid, bo 2-ethylhexyl acrylate/vinyl acetate/allyl methacrylate/acrylic acid,

2-Ethylhexyl acrylate/vinyl acetate/2-hydroxyethyl acrylate, 2-ethylhexyl acrylate/vinyl acetate/2-hydroxyethyl methacrylate, 2-ethylhexyl acrylate/fumaric acid diethyl ether/acrylic acid, 2-ethylhexyl acrylate/maleic acid diethyl ether/2-hydroxyethyl acrylate.

As an example of the best crosslinking agents, the following compounds can be named: diphenylmethane-4-diisocyanate, hexamethylene diisocyanate, titanium acetylacetonate, aluminum acetylacetonate, iron acetylacetonate, zinc acetylacetonate, magnesium acetylacetonate, zirconium acetylacetonate, 2-ethyl-1,3-hexanediol titanate, tetraisooctyl titanate, tetranonyl titanate, polyfunctional propylene imine derivatives, ether derivatives of 7/0 melamine-formaldehyde resins, highly methylated urethane resins, and imino-melamine resins.

Non-crosslinkable contact adhesives are preferably obtained by polymerization of monomers in the following combinations: 2-ethylhexyl acrylate/M-butyl acrylate/vinyl acetate, 2-ethylhexyl acrylate/vinyl acetate, 2-ethylhexyl acrylate/M-butyl acrylate/vinyl acetate/allyl acrylate, 2-ethylhexyl acrylate/M -M-butyl acrylate/alsmethacrylate, 2-ethylhexyl acrylate/M-butyl acrylate/vinyl acetate/divinylbenzene, 2-ethylhexyl acrylate/fumaric acid diethyl ether/allyl acrylate, 2-ethylhexyl acrylate/maleic acid diethyl ether/allyl acrylate, 2-ethylhexyl acrylate/M-butyl acrylate/acrylamide /vinyl acetate/allyl acrylate, 2-ethyl hexyl acrylate/N-butyl acrylate/isobutyl acrylate/vinyl acetate/allyl acrylate.

In addition, some contact adhesives of the above type can be used in the form of water dispersion (dispersion type contact adhesives). The advantage associated with the use of such dispersion-type contact adhesives is that in the process of applying coatings from them and their drying, there is no evaporation of flammable or toxic solvents.

Dispersion-type contact adhesives should preferably be obtained by polymerization of monomers in the following combinations: p

M-butyl acrylate/isobutyl acrylate/acrylic acid, 2-ethylhexyl acrylate/M-butyl acrylate/acrylic acid, (8) 2-ethylhexyl acrylate/M-butyl acrylate/2-pdroxyethylacrylamide, 2-ethylhexyl acrylate/M-butyl acrylate/vinyl acetate/acrylamide, 2-ethylhexyl acrylate /N-butyl acrylate/vinyl acetate/2-hydroxyethyl acrylate, 2-ethylhexyl acrylate/N-butyl acrylate/allyl acrylate/acrylic acid, 2-ethylhexyl acrylate/M-butyl acrylate/vinyl acetate/divinylbenzene. "AND

To improve the physical properties of the contact adhesive or to match them with special requirements, the polyacrylates suitable for use according to the invention are cross-linked with multivalent metal ions. Usually, metal ions are used in the form of chelate compounds of metals, soluble in organic compounds

With solvents. The most suitable for use as crosslinking agents are aluminum acetylacetonate and titanium coacetylacetonate.

When used in accordance with the invention as a contact adhesive of polyacrylate contact adhesive, its ability to dissolve the active substance depends mainly on the type and number of free functional groups contained in such an adhesive. "

Polyacrylates with polar groups, primarily with free hydroxy groups, are among the best for use in the contact adhesive device proposed in the invention. As an example of such contact adhesives, we can mention polyacrylates, for the preparation of which polar monomers, such as, for example, hydroxyethyl acrylate, hydroxyethyl methacrylate, acrylic acid or methacrylic acid, are used in an amount of about 1-10% by weight, especially preferably in an amount of 3% by weight , most preferably in the amount of 4-Yemas.9o. similar

Contact adhesives are sold under the trade name Oygo-Takef (Mayopa! ziagop 8 Spetis!v, Hamburg). In the device proposed in the invention, it is most desirable to use contact adhesives of the polyacrylate type, in the preparation of which hydroxyethyl acrylate and/or hydroxyethyl methacrylate monomers are mixed in the polymerization process in the amount of 3-wt.95, especially preferably in the amount of 4-wt.9o. Similar contact adhesive can be obtained according to the general method described in (05 5498418) as follows. Contact glue of the specified type can be obtained by radical polymerization. At the first stage in an organic solvent, a mixture of 21-40 wt.9o5 vinyl acetate, 55-7Omas.9o CoCo-Salkyl ether of acrylic acid and 3-Omas.bo Co-Su/hydroxyl alkyl ether of acrylic acid is prepared (the content of monomers in the mixture should make up a total of 1OOmas.9b).

At the second stage, a common cross-linking agent in an organic solvent is mixed into the mixture, and in some cases, an active substance is mixed, the quality of which must correspond to the intended use of the transdermal device (patch), if necessary, in an organic solvent.

GF) At the end of the third stage, the resulting mixture of a special acrylate copolymer with vinyl acetate is subjected to

Ф an additional stage of crosslinking with simultaneous heating and removal of the organic solvent or mixture of solvents that are used. The obtained active substance is "embedded" in the material of the contact adhesive in a special way by means of sequential and additional cross-linking of the specified acrylate copolymer with vinyl acetate.

In another variant, the copolymer of acrylate with vinyl acetate can be polymerized and cross-linked in the absence of the active substance. In this case, the active substance is added during the processing of the acrylate copolymer with vinyl acetate during the production of the patch. The relative viscosity of this copolymer of acrylate with vinyl acetate b5 is from 3.0 to 4.2 at 2026.

In addition to vinyl acetate, it is desirable to add 2-ethylhexyl acrylate and hydroxyethyl acrylate monomers to the mixture.

For subsequent crosslinking of a special copolymer of acrylate with vinyl acetate, it is advisable to use titanium acid ether consisting of polybutyl titanate and/or titanium acetylacetonate, preferably in an amount from 0.3 to Zmas.bo based on the weight of the copolymer.

The manufacturing process of the TTS proposed in the invention may include the following stages. First, prepare a solution of the copolymer obtained by radical polymerization of a mixture of monomers, consisting of 21-40 wt.9o vinyl acetate, 55-7 wt.o Co-C alkyl ester of acrylic acid and 1-10 wt.bo Co-C.hydroxyalkyl ether of acrylic acid, with admixture in in some cases, the active substance in the amount necessary for the intended purpose of using TTS, as well as a common crosslinking agent or a mixture of such agents, after which the resulting solution is applied to the protective film of TTS with a layer of the required thickness, and finally, by heating, the solvent or mixture of solvents is removed , which ultimately leads to additional crosslinking of a special copolymer of acrylate and vinyl acetate.

In one of the variants of the implementation of a similar process, the copolymer of acrylate with vinyl acetate and, in some cases, the active substance, as well as the crosslinking agent, are first dissolved in a solvent containing 20-4Omas.9o /5 ethanol or a mixture of ethanol and methanol, with a certain ratio between solid components, consisting of 40-bOmas.bo from a mixture of acrylate copolymer with vinyl acetate, a crosslinking agent and an active substance.

In another, better, variant of the implementation of the invention, the active substance is added to the dispersion only after the crosslinking of the acrylate and then, after homogenization, it is applied to the protective film.

A special example, included in this description as a reference, of obtaining a similar contact adhesive based on a copolymer of acrylate with vinyl acetate is given in (patent 5 5498418, starting with line 61 in column 2 and ending with line 10 in column 3.

The most preferred contact adhesives for use according to the invention are Yuigo-Take 387-2287 and Oigo-Take 387-4287 adhesives (manufactured by Maiopai! Ziagsp 8 Spetis! Iz, Hamburg). In one of the particularly best variants of the invention, Yugo-Tak contact adhesive is mixed in a solvent suitable for this purpose with the required amount of active substance, and the homogeneous dispersion obtained in this way is distributed in an even (8) layer of the required thickness. Finally, at an elevated temperature (50-702C), the solvent or mixture of solvents is removed.

According to this, another object of the invention is a device for transdermal introduction into the body of a compound of the formula | "and Kk Ge"! "-- with no f o so ov

I « yu Z z - s i f Kh

М со - с In which A is hydrogen or deuterium, and K is a group selected from C 4 -Salkyl, C 3 -Stocycloalkyl, and phenyl, each of which may be substituted by C 1 -C salkoxy group, fluorine, chlorine, bromine, iodine , a nitro group, an amino group, a hydroxy group, an oxo group, a mercapto group or a deuterium, and in which the C atom marked with the symbol "" (asterisk) is in the (K)-configuration, which differs in that the compound of the general formula (o) is introduced into the polymer layer , preferably in a polymer layer that is capable of self-adhesive, (adhesive matrix) containing at least one polymer of the acrylate type and/or methacrylate type. 5 The compound of formula I is preferably introduced into the acrylate matrix in the form of a free base, especially preferably in the form of a highly pure free base.

GF) In the best version, fesoterodine is introduced as an active substance in the acrylate-based matrix proposed in the invention in the form of a free base, most preferably in the form of a highly pure free base. days Figure 3 shows a graph of the rate of penetration of the active substance through the skin of a mouse, built on the basis of data obtained by ip migo when applying a patch, which is made on the basis of acrylate glue by a method based on the use of its melt and contains fesoterodine introduced into it in the form of highly pure free foundations.

Excipients and impurities

The polymer matrices described above, which contain the active substance, in the devices proposed according to the invention may also contain other auxiliary substances and impurities. As an example, we can name b5 buffers, hydrotropic solubilizers, crystallization inhibitors, chemical stabilizers, antioxidants, other auxiliary substances for slowing down the release of the active substance (retardant), as well as activators of percutaneous absorption.

Percutaneous absorption activators can be added, for example, to increase the amount of active substance penetrating through the skin or to reduce the size of the device and, accordingly, the area of the skin covered by it. By way of non-limiting examples, the most commonly used percutaneous absorption activators include alcohols, primarily short-chain alcohols such as ethanol, fatty alcohols such as lauryl alcohol, polyhydric alcohols such as glycerin, amides such as aromatic amides , such as M,M-diethyl-m-toluamide, amino acids, azones, oils (oils), such as, in particular, menthol 70 or peppermint oil, fatty acids and their esters, such as, for example, oleic acid, lauryl acid, isopropyl myristate or glycerol monolaurate, macrocycles, such as, for example, cyclopentadecanone, phospholipids, such as lecithin, 2-pyrrolidones, and sulfoxides, such as, in particular, dimethyl sulfoxide.

Due to the good ability of free bases of the general formula | to penetrate through the skin in the best embodiments of the invention, it is proposed to abandon the admixture of percutaneous absorption activators.

As other components, a hydrophilic component, such as a hydrophilic polymer, can be added to the adhesive matrix. Similar hydrophilic polymers can perform the functions of hydrotropic solubilizers, respectively, inhibitors of crystallization of compounds of the general formula !| and contribute to their uniform distribution in the adhesive matrix.

Hydrophilic polymers suitable for use in the proposed TTS of the invention can be selected, for example, from the group that includes polysaccharides, substituted polysaccharides, polyethylene oxides, polyvinyl acetates, polyvinylirolidones (PVP), PVP with appropriate plasticizers, polyethylene glycols, polypropylene glycols, polyacrylates, polyvinylpyrrolidone copolymers and (poly)vinyl acetate, copolymers of ethylene and vinyl acetate, as well as polyvinyl alcohols with appropriate plasticizers, for example, glycerin.

The best hydrophilic polymers include PVP, polyethylene oxides (PES), polyvinyl acetates (PVC), as well as copolymers of PVP with vinyl acetate.

Hydrophilic polymers can be added to the adhesive layer, for example, in an amount from 0.5 to 4Omas.bo in o) conversion to its total weight. It is desirable to add hydrophilic polymers in an amount from 2 to 25 wt.9b, especially preferably from 2 to 15 wt.95 or from 2 to 1Omas.9b5.

Such hydrophilic polymers are especially suitable for processing by a method based on the use of a melt, so

The dynamic melt viscosity of which at temperatures below 1702 is a maximum of 150 Pa.s, better less than 120 Pa.s, especially better less than 80 Pa.s. If the dynamic viscosity of the hydrophilic polymer is too low at the necessary temperature of its processing, it is necessary to add a suitable plasticizer to it beforehand, for example, glycerin.

Admixture of the above-mentioned hydrophilic polymers may be expedient, first of all, in the case of z5 Adhesive matrices that have very high hydrophobicity, for example, silicone, polyisobutylene or z3x5 matrices.

Complex 3,3-diphenylpropylaminomonoesters in the form of free bases reveal what was already mentioned in

ИМУО 01/35957)|), a tendency to decrease its content, which is due, for example, to hydrolysis and transesterification. According to the invention, however, it was unexpectedly found that the stability of complex "

C,3-diphenylpropylaminomonoesters can be significantly increased when they are included in a matrix with hydrophilic components. So, for example, if after a month of storage at 5 C, the free base of fesoterodine in the form of oil "decomposes to approximately 3-4965, then when fesoterodine is introduced into matrices containing polar components, its amount does not decrease at all or decreases by much to a lesser extent.

As an example of such matrices that provide stabilization of the complex monoether of the general formula I, one can (se) name matrices that contain polyacrylates, primarily polyacrylates with polar groups, EVA or mixtures of -3 silicone adhesives with hydrophilic polymers, for example, PVP, PVAc or PEO ( table 4).

F i. and with storage at C bO90-th relation. humidity blue 11111 van. ov o yu teliobutlenv 00000011 urn vv 00001711 piano 60 material (oil) for the average monthly decrease in its content when stored in matrices, 65

From the data presented in Table 4, it follows that the introduction of fesoterodin in matrices consisting of

EVA glue, polyacrylate glue or mixtures of silicone glue with hydrophilic polymers, such as PEO or PVP, allows to significantly increase the stability of fesoterodine, namely, regardless of the processing method (in melt or solvent).

Accordingly, one of the variants of the invention refers to devices in which the content of the compound of the general formula I! in the form of a free base decreases much more slowly compared to their storage in the form of oil under identical conditions in a state not introduced into the polymer. The best options include those in which, when stored at 59C and/or 2593, at least a 2-, 3-, 7-, or 10-fold increase in the stability of the complex 3,3-diphenylpropylaminomonoether is provided in comparison with similar indicators when it is stored in free form .

Especially the best devices proposed in the invention include those in which the free base is present in the polymer layer, in which the content of the compound of the general formula I! after b-month storage at 4 "C decreases /5 Less than by 395, better by less than 2905 or 1905, and after 3-month storage at 2592 and 6095 relative air humidity decreases by less than 1095, better by less than 595, especially better than 39o or 1.590 less.

The best matrixes are those that contain from 50 to 95 wt.95 of a contact adhesive selected from the group that includes - acrylate adhesives, as well as their copolymers, primarily acrylate adhesives with polar groups, for example, with

Free hydroxy groups, - EVA adhesives, - silicone adhesives, which contain from 2 to 25 wt.bu, preferably from 2 to 1Omas.9bo, of a hydrophilic polymer, selected primarily from PEO, PVP and PVACcs, - 5BH5- or PIB-glues, which contain from 2 to 25wt.9o, preferably from 2 to 1Owt.95, of a hydrophilic polymer, or a mixture of hydrophilic contact adhesives (for example, polar polyacrylates) and hydrophobic contact adhesives (for example, silicone, ZX5 or ShbB glues). (at)

The best contact adhesives for obtaining the matrices proposed in the invention include polyacrylates, primarily polyacrylates with polar groups. Such matrices not only provide an exceptionally effective release profile of fesoterodine, but also have a high ability to stabilize the complex sozo Z,Z-diphenylpropylaminomonoester.

The present invention also relates to the use of free bases of formula I for the preparation of transdermal dosage forms with controlled release of the active substance from them. b

Another object of the invention is, according to this application, the compound of the formula | presented as a free base h- so and k no o "

АХ -в с 7 осв п "У И, со Х - х » Ж их 50 со in which K is C-Salkyl, C3-Scycloalkyl or substituted or unsubstituted phenyl and in which is marked with the symbol """ (asterisk) C -atom is in the (K)-configuration, to obtain a medicinal product intended for transdermal administration of this compound into the body, which is characterized by the fact that the compound of the general formula 59 in the form of a free base is added to a polymer layer, preferably to a polymer layer capable of self-adhesive

GF) (adhesive matrix).

The compound of the general formula | it is preferably presented in the form of a free base with a degree of purity of at least 9Vmas.9o, preferably at least 9995, especially preferably 99.595, most preferably at least 99.8905.

In one of the best options, the free base of the general formula | used for the preparation of a transdermal medicinal product, which (a) has a maximum surface area of 40 cm, (b) has a polymer layer that is capable of self-adhesive, that (61) has a specific gravity from 30 to ЗОbg/m2, 65 (62) contains from 50 up to 95% by weight of contact adhesive, (63) contains from 5 to 40% by weight of compounds of the general formula | in terms of the total mass of the polymer layer, and (c) is capable of releasing the specified compound of the general formula | for at least 24 hours with a constant rate of its penetration through human skin, which is at least 125 μg/h.

A typical and best example of such a better medicinal product is the so-called monolithic plaster, which consists of an adhesive matrix (1) that contains an active substance, an adhesive matrix inert to the components, and a back layer (2) impermeable to them, as well as a protective layer ( 3), which is removed immediately before the use of the medicinal product (Fig. 4).

To obtain the transdermal medicinal products proposed in the invention, it is especially desirable to use (KO-2-I3-(1,1-diisopropylamino)-1-phenylpropyl/|-4-(hydroxymethyl)phenylisobutyrate in the form of a highly pure free base (fesoterodine).

From the data shown in Fig. 2 and in Table C, it follows that the application of free bases of the general formula I proposed in the invention (in this case, fesoterodine) makes it possible to obtain transdermal medicinal products, which, when the content of the active substance in them is equal to 15 wt.95, and surface area equal to 20 cm?, provide 75 transport of the compound of the general formula | through the human skin with a rate of penetration through it, which is from b to mg per day. Thus, by varying the surface area of the dosage form in the range from 5 to 30 cm2, the rate of penetration of the active substance through the skin can be adjusted in a simple way and without changing the formulation in such a way that the active substance enters the body for at least one day or two days in a daily dose of 0 .2 to 2Omg (table 3).

In addition, varying the concentration and content of the active substance in the device proposed in the invention allows you to additionally adjust the duration of the stage of "flow" of the active substance to the skin and/or the duration of the release of the active substance from the device.

The devices proposed in the invention, respectively, the drugs, are most suitable for the treatment of urinary incontinence, primarily involuntary urination, detrusor hyperactivity, pollakisuria, nocturia, or the imperative urge to urinate. at

The invention further relates to the manufacture of devices proposed in the invention for transdermal introduction of an active substance into the body.

Another object of the invention is a method of prevention and/or treatment of urinary incontinence, primarily involuntary urination, detrusor hyperactivity, pollakisuria, nocturia or the imperative urge to (co) urinate, by introducing into the body of a mammal, primarily a human, in need of prevention or treatment of the specified diseases, the compound of the general formula I described above and/or applying the proposed a in the invention of the device containing it to the skin of a mammal, primarily to the skin of a person. b

Examples 1. Preparation of fesoterodine in the form of a highly pure base -

A. Preparation of fesoterodine in the form of a base (formula B, see Fig. 1, K is isopropyl) c

To a cooled to -3065°C solution, 59.8 g (175.mol) of (KO-2-IZ-(diisopropylamino)-1-phenylpropyl|-4-(hydroxymethyl)phenol (formula A, see Fig. 1) dissolved in 750 ml of dichloromethane, a solution of 18.6 g of isobutyric acid chloride in 250 ml of dichloromethane was added dropwise over the course of about 10 minutes with stirring and cooling in an ice bath. After about 5 minutes, a white substance precipitated. a solution of 17.7 g of triethylamine in 250 ml of dichloromethane was added to an ice bath. Then the mixture was successively washed once with 250 ml of water, 250 ml of an approximately 595% aqueous solution of MnSO" and 250 ml of water. to a constant mass resulting in a viscous oil of pale yellow color.

Yield of crude product: 63.7 g (88.595 from theoretical). o The purity of the compound of the formula B according to the data of HCVR analysis was 94.195 in this example. (Normal - the purity range of this compound is 90.5-94.4905).

B. Preparation of fumarate (formula E, Fig. 1. K represents isopropyl, X means hydrofumarate anion) (se) A solution of 41.87 g (102 mmol) of ether (K)-2-(3-diisopropylamino-1-phenylpropyl)- 4-hydroxymethylphenylisobutyric acid (formula B) in 30 ml of 2-butanone was mixed under heating with fumaric acid (11.81 g, 102 mmol). After dissolution of the acid, cyclohexane (20-30 ml) was slowly added with stirring until the beginning (I e) of turbidity. The colorless homogeneous mixture was first kept for 18 hours at room temperature, and then for several hours at 09C. The colorless crystals that precipitated were separated by vacuum filtration, washed with a small amount of a mixture of cyclohexane and 2-butanone (in a ratio of 90:10, at 22 rpm) and dried in a vacuum at 302C. o Yield: 44.6 g (83.190 from theoretical) hydrofumarate (formula E) of ether (K)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyric acid in the form of colorless flakes. ko Ill 98.82С, after the second crystallization from the same mixture of solvents, a product of 10390 was obtained.

Io 9- 6.0 (c - 1.0, ethanol); -19.3 (c-1.0, acetonitrile). 60 "H-NMR (SOSIV5): in particular 6.84 parts per million for the CH-tidrofumarate anion. 13S-NMR (SOSIVv): in particular 135.58 parts/million and 170.5b6 parts/million for the olefinic and carbonyl carbon atoms of the hydrofumarate anion .

The purity of the compound of formula E obtained in this example (according to the data of РХPR-analysis) was 99.2905. 65 B. Preparation of fesoterodine M in the form of a highly pure base (formula B. Fig. 1. K is isopropyl) 250 g (0.474 mol) of crystalline fumarate

(K)-2-3-(diisopropylamino)-1-phenylpropyl|-4-(hydroxymethyl)-phenyl-2-methylpropanoate (formula EE) was added with stirring to 1 L of water and heated to 302. After about 30 h, an almost transparent solution. 96.0 g of sodium hydrogen carbonate was added to this solution, cooled to room temperature, in portions during about 10 minutes with stirring. 1 liter of dichloromethane was added to the almost transparent colorless aqueous solution. After brief stirring at room temperature (intense formation

СО»5) the dichloromethane phase was separated and successively washed once with 0.2 l of a 590% aqueous solution of sodium bicarbonate and 0.2 l of water. After filtration, the clear colorless dichloromethane phase was concentrated on a rotary evaporator at a bath temperature of about 402 to a constant mass with the creation of 70 degrees of vacuum using a membrane pump (final pressure 5 mbar). As a result, ester (KO-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyric acid (formula B) was obtained in the form of an almost colorless viscous oil.

Yield: 180.6 bg (92.695 from theoretical). so U--5.9 (s-1.0, ethanol); -6.7 (c-1.0, acetonitrile).

NMR (SOCI5): 19.01, 19.95, 20.59, 21.12, 34.28, 36.89, 41.88, 42.32, 43.90, 48.78, 64.68, 122 .57, 125.59, 126.16, 126.86, 127.96, 128.54, 136.88, 138.82, 143.92, 147.90, 175.69 (ppm).

The purity of the compound obtained in this example was 99.095 according to the data of the HCVR analysis. The usual purity range for this compound is 98.7-99.590.

TH-th C-NMR: Resonance signals for the hydrofumarate anion were not detected (cf. formula E).

For the long term, this compound is best stored in a dark place in an argon atmosphere at -2026.

The "H- and C-NMR spectra revealed the absence of resonance signals of the hydrofumarate anion (compare with the spectra of compound E).

Long-term storage of the obtained product was mainly carried out in a dark place under argon at -20 eB. with

D. Production of hydrocarbonate (formula E, Fig. 1, K is isopropyl, X means hydrocarbonate) Ge)

Fesoterodine (107.7 mg, ether (K)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyric acid, formula B) is covered with a layer of distilled water and stirred at room temperature. After 2 days of stirring, the reaction mixture still remains biphasic. According to thin-layer chromatography (silica gel, solvent system: petroleum ether/acetone/triethylamine in the ratio of 70:20:10, vol..905), there is no organic material (formula B or E) in the upper, aqueous phase. chi

A weak stream of carbon dioxide is passed through this two-phase reaction mixture at room temperature and with stirring. Dissolution of the lower, oily phase (fesoterodine) in the aqueous phase is complete until the formation of a transparent solution is completed after two days. h- 13C-NMR spectrum of fesoterodine hydrochloride (value 5): 14.11, 15.36, 15.51, 29.32, 31.09, 38.95, so 43.31, 52.38, 60.45 , 120.04, 124.07, 124.33, 124.83, 126.12, 131.97, 136.55, 139.06, 144.60, 157.46 (NSO"), 175.75.

The obtained values (value 5) are in good agreement with the data of "NMR-spectroscopy of fesoterodine hydrochloride obtained by dissolving the base in 1-molar hydrochloric acid: 13.26, 15.32, 15.48, 29.29, 31.06, 38.95, 43.34, 52.42, 60.49, 120.10, 124.18, 124.38, 124.85, 126.13, 131.97, 136.50, 139.02, 144, 61, 175,94. " 2. Preparation of TT matrices in s 2.1. Preparation of a matrix based on silicone glue by a method based on the use of a melt of 8.5 g of contact adhesive on a silicone base, which is a mixture of contact silicone adhesive Bio-ACP "" О07-4300 (Yom Sogpipd company, Michigan) with 5 wt. 90 ozokerite (Ozhm Soptipo company) was heated to 1502 for about 20 minutes until a homogeneous melt was formed. Then 1.5 g of fesoterodine (highly pure free base) was added and the mixture was kept for the next 5 minutes at 15020. Then the mixture was homogenized by hand and applied to a preheated film (1202, gap width 250 μm). For experiments on the release of the active substance, the film was cut into pieces with an area of 5 cm. 2.2. Obtaining a matrix based on acrylate glue by a method based on the use of a solvent (se) 1.5 g of fesoterodin in the form of a highly pure base was dissolved in dichloromethane and added to 8.5 g of a solution of their glue" 20 YuigotakF 387-2287 (in ethyl acetate). The resulting mixture was stirred until a homogeneous dispersion was obtained.

Then this dispersion was applied in an even layer on the film (extraction according to Erichsen 100 μm, bmm/s, drying: ЗОхв 12; at 502). 2.3. Obtaining a matrix based on 5X5 glue by a method based on the use of a melt of 100 parts of styrene block copolymer (with a structure of styrene-polyisobutylene-styrene, type Kgaiop 011072), 150 25 parts of resin (type Kedaiye K 1090), 20 parts of oil (type Opaipa) and 1 part of antioxidant (Igdapoh type)

GF! were mixed together and melted at a high temperature equal to 1402. Then, 1.5 g of fesoterodine (in the form of a highly pure free base) was added to the melt taken in portions of 8.5 g, and the mixture was kept at 14092 C for the next 1 minute. Then the mixture was mechanically homogenized and applied to a preheated film (1202C, 25O0μm). For experiments, the film was cut into pieces of the required size. 2.4. Obtaining a matrix based on EVA glue by a method based on the use of melt 8.5 g of EVA glue was heated for about 20 minutes to 1602C until a homogeneous melt was formed. Then 1.5 g, respectively 1.65 g of fesoterodine in the form of a highly pure base was added to this melt, after which the mixture was homogenized by hand. At the end, the mixture was applied to the preheated (up to 120 22) surface 65 of the cooling cylinder of the "Sp-KoiI" type. The resulting film (for experiments on the penetration of the active substance through the skin) was cut into pieces with an area of 5 cm7,

C. Experiments on the study of the release of the active substance 3.1. Determination of the penetration of the active substance on the mouse skin model. The rate of penetration of the active substance through the skin of the mouse was determined in a horizontal diffusion cell, using pieces of skin with a thickness of about 120-15μm, taken from the abdomen and back of animals. Medium: phosphate buffer solution (0.066 molar), pH 6.2, 3226.

The release of the active substance was determined by high performance liquid chromatography (HPLC). 3.2. Determination of the penetration of the active substance on the human skin model (a) Experimental part 70 The penetration of fesoterodine through the human skin was determined mainly according to the method described in |N.

Tapoo and others. in the docsgp. Sopigo! Kei. 45, 1997, ee. 41-47), but using instead of silicone membranes a dialysis membrane |Oiaspeta, type 10.14, firm Oiapogt, Munich, Germany, made of neutral cellulose, the limiting size of molecules that pass through the membrane, 5000Da, thickness (in the dry state) 25μm, previous processing according to the manufacturer's instructions).

In the experiments, pieces of human skin with a thickness of about 25 µm, taken from the abdominal area, were used.

TTS with a surface area of 2.545 cm2 was applied to a piece of skin of the same area, while the skin was adjacent to the silicone membrane on its side facing away from the acceptor (scheme 1). SFR (phosphate-buffered saline, 0.06b6-molar) with pH 6.2 and temperature 32 0.590 was used as an acceptor phase. Experiments were carried out for 72 hours at a flow rate equal to 5 ml/h, taking samples every At the time of sampling, the medium into which the active substance was released was replaced with a fresh medium with a temperature of 32 0.590 and the amount of fesoterodine released was determined using HCVR.

The rate of penetration С() was determined in terms of the area of the measuring cell (0.552 cm 2 ) according to the following formula:

Ф(О (μg/cm"|"concentration of fesoterodinovolume of the acceptor/0.552cm? s

Scheme! (o) (ge)

WHAT | nlastyr, area -2.545 cm! "

Up to 1 human skin, F o g area w- 2.545 cm", 250 μm - x . so . o. silicone membrane,

SI area - 2.545 cm", 150 μm diffusion cell, « 5. area -1М31 cm" - с 7 "z with acceptor, area -0.552 cm p oo (b) Analysis of the release of the active substance

Penetration of the active substance through skin preparations was determined using РХВР (column ZrPegigog - 5CM, 25cm) under the following conditions: 406. parts of acetonitrile/b vol. parts of H»O/0.19606. parts of TFOK, 352, 225nMm, "se flow rate Tml/min. 4. Determining the purity of the active substance. The chemical purity of fesoterodine was determined using РХPR, which is based on the separation of components on a stationary reverse phase and gradient elution with a solvent system.

Materials and equipment (as an example)

Acetonitrile for РХР, methanesulfonic acid («9995, RiiKa company), water (purified, suitable for РХР

QUALITY), pump UUaiegv 510, furnace for heating the column (heating module U/a (eg Soishtp Neaieg Modii, 35 2), sample dispenser (Uaieg MUizr 717, injected volume, 20 μl), UV detector (Zpitaigi ZRO 10A), column

Ф) (150x3.9mm, Zpieidy KR8 paper, number according to the catalog of the Uaiege company: UMAT 200655). km Mobile phase

Acetonitrile from 0.0595 methanesulfonic acid (vol. 90), component A. 60 Water from 0.0595 methanesulfonic acid (06.95), component B.

Gradient elution program: time (min) 0.0 - 15965 component A and 8595 component B, after 15 min - 6090 component A and 4095 component B, after 20 min - 1595 component A and 8595 component B, flow rate 1.2 ml/min.

The concentration of each of the reference solvents of the compounds of formulas A, B and C (Fig. 1, K is isopropyl) 65 was from 10 to 25 Ωkg/ml. At higher concentrations, "tails" with overlapping peaks were observed.

Data Processing

To analyze the data obtained by the 10095 method, the average values of the areas of all chromatographic peaks (according to the results of three measurements) were summed up and the obtained value was taken as 10095. The areas of individual peaks (U 901 were related to this value. Retention time for compounds of formulas A, B and C (u min): 5.9, 9.0 and 12.6. 5. Determination of residual salt content

By TN-NMR spectroscopy at a resonance frequency of 200 MHz or 500 MHz, the spectra of fesoterodine were recorded as a pure base in SOCI as a solvent, and as a result of electronic integration of groups of characteristic resonance signals, the following values were obtained: 70 5-6.97 ppm (doublet, aromatic hydrogen , no, 1n), 5-4.59 parts/million (singlet, HO-CH", 2H), 5-4.10 parts/million (triplet, H"-propyl, 1H).

The residual salt content (in mol.9o) can be calculated by referring the obtained values to the resonance signal of an anion, for example, hydrofumarate (5-6.84 parts/million, "CH-, 2H).

Claims (11)

The formula of the invention 1. Device for transdermal administration 20. (K)-2-I3-(1,1-diisopropylamino)-1-phenylpropyl I|-4-(hydroxymethyl)phenylisobutyrate (fesoterodine), which differs in that fesoterodine is in a polymer matrix and is released through the human skin in a dose , which is from 0.5 to 20 mg per day. 2. The device according to claim 1, which differs in that it is manufactured by mixing fesoterodine in the form of a free base into the polymer matrix. with C. The device according to any of the previous items, which is characterized by the fact that the polymer matrix contains from 55 to 90 wt. 9o contact adhesive and is capable of self-adhesive. 4. The device according to any of the preceding points, which is characterized by the fact that the polymer matrix contains one or more contact adhesives selected from the group that includes acrylates, copolymers of ethylene with vinyl acetate (EVA), silicones and block copolymers of styrene (ХХ5). co 5. The device according to any of the previous items, which differs in that the polymer matrix is 50-95 wt. 95 " consists of a melt-able mixture of silicone contact adhesive and at least one plasticizer. b" 6. The device according to any of the previous items, which differs in that the polymer matrix is 50-95 wt. 95 "- consists of (a) hydrophilic contact adhesive and/or (b) a mixture of hydrophobic contact adhesive with 2-20 wt. 90 hydrophilic polymer based on the total weight of the polymer matrix, and/or (c) a mixture of hydrophilic and 9 hydrophobic contact adhesives. 7. The device according to claim 6, in which the hydrophilic polymer is PEO, PVP or PVAC. 8. The device according to any of the previous points, which is characterized by the fact that the degree of purity of the fesoterodin introduced into the polymer matrix is more than 97 wt. 90. 9. The device according to any of the previous items, which is characterized by the fact that it - c (a) has a surface area of at most 50 cm, » (b) has a polymer layer capable of self-adhesive, which (61) has a specific gravity of 30 up to 300 g/m?, (62) contains from 50 to 95 wt. 95 of contact glue, 15 (63) contains fesoterodine in a concentration of 5 to 40 wt. 95 based on the total weight of the polymer layer, and (c) is capable of releasing fesoterodine for at least 24 hours. with a constant rate of its penetration through human skin, which is at least 4 μg/cm/h. at 50 10. The device according to any of the previous points, which is characterized by the fact that its surface area is FT" a maximum of 40 cm, and the content of the active substance in the self-adhesive polymer matrix is from 7 to 30 wt. 90. (fr 11. The device according to any of the previous items, which is characterized by the fact that it is able to provide for at least 24 hours. entry into the body of fesoterodine in a dose of at least 3 mg per day with a constant rate of its penetration through the human skin. 12. The device according to any of the previous items, which is characterized in that it has an adhesive matrix (1), that GF) contains an active substance, a back layer (2), inert to the ingredients of the adhesive matrix and impermeable to them, and protective layer (3), which is removed immediately before using the device. 13. Device for transdermal administration of (KO-2-I3-(1,1-diisopropylamino)-1-phenylpropyl/|-4-(hydroxymethyl)phenylisobutyrate (fesoterodine) In the form of a free base for at least 24 hours with constant the speed of its penetration through the skin, which is at least 4 μg/cm/h, and the device contains fesoterodine in a polymer matrix. 14. Use of (KO-2-I3-(1,1-diisopropylamino)-1-phenylpropyl/|-4-(hydroxymethyl)phenylisobutyrate (fesoterodine) for the preparation of a medicinal product intended for transdermal introduction of 65 fesoterodine into the body for prevention or treatment urinary incontinence, primarily involuntary urination, detrusor hyperactivity, pollakisuria, nocturia or an imperative urge to urinate, which differs in that fesoterodine is in the drug in a polymer matrix. 15. Application according to claim 14, which differs in that fesoterodine is added to the polymer matrix in the form of a free base. 16. Use according to any of the previous items, which is characterized by the fact that the polymer matrix is self-adhesive. 17. Application according to any of the previous items, which differs in that the polymer matrix containing the active substance is obtained by the method of its processing in a melt. 18. Application according to any of the previous items, which differs in that the polymer matrix, which contains the active substance, is obtained by processing it in a solvent. 19. Use according to any of the previous items, which is characterized by the fact that fesoterodine is released in a dose of at least 3 mg per day with a constant rate of its penetration through human skin for at least 24 hours. 20. Application according to any of the previous items, while the polymer matrix contains a contact adhesive /5 C of the group, which includes polyacrylates, copolymers of ethylene with vinyl acetate (EVA), polyisobutylenes, silicones and block copolymers of styrene (5X5). 21. Application according to any of the previous items, which is characterized by the fact that the polymer matrix contains from 50 to 95 wt. 95 contact adhesive selected from the group that includes (a) polyacrylates, (b) contact EVA-adhesives, (c) contact silicone adhesives, (d) contact 5ХZ-CLs, (e) contact PIB-glues, while to hydrophobic of contact adhesives (c), (d) and (e) add 2-20 wt. 95 hydrophilic polymer in the calculation of the total weight of the polymer matrix. 22. The use of any of the preceding claims, wherein the device (a) has a surface area of at most 50 cm, (b) has a self-adhesive polymer matrix that (61) has a specific gravity of 30 to 300 g/m , c (62) contains from 50 to 95 wt. 95 of contact glue, (63) contains fesoterodine in a concentration of 5 to 40 wt. 95 based on the total weight of the polymer matrix, and (c) releases fesoterodine for at least 24 hours. with a constant rate of its penetration through human skin, which is at least 4 μg/cm2/h. -- 23. The method of manufacturing the device according to any of claims 1-13, which is characterized by the fact that fesoterodine presented in the form of a free base is introduced into the polymer matrix c. 24. A method for the prevention or treatment of urinary incontinence, primarily involuntary urination, detrusor hyperactivity, pollakisuria, nocturia or the imperative urge to urinate, which is characterized by using the device according to any of claims 1-13, applying it to the skin of a mammal. - with ;" so - (Se) them 50 ii») F) ko 60 b5